EP3691614A1 - Pharmazeutische zusammensetzung mit vildagliptin und verfahren zur herstellung davon - Google Patents

Pharmazeutische zusammensetzung mit vildagliptin und verfahren zur herstellung davon

Info

Publication number
EP3691614A1
EP3691614A1 EP18788663.5A EP18788663A EP3691614A1 EP 3691614 A1 EP3691614 A1 EP 3691614A1 EP 18788663 A EP18788663 A EP 18788663A EP 3691614 A1 EP3691614 A1 EP 3691614A1
Authority
EP
European Patent Office
Prior art keywords
vildagliptin
disintegrant
pharmaceutical composition
weight
tablet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP18788663.5A
Other languages
English (en)
French (fr)
Other versions
EP3691614B1 (de
Inventor
Evangelos Karavas
Efthymios Koutris
Vasiliki SAMARA
Ionna KOUTRI
Anastasia Kalaskani
Andreas KAKOURIS
Vasilis MPENEKIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmathen SA
Original Assignee
Pharmathen SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmathen SA filed Critical Pharmathen SA
Publication of EP3691614A1 publication Critical patent/EP3691614A1/de
Application granted granted Critical
Publication of EP3691614B1 publication Critical patent/EP3691614B1/de
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a solid pharmaceutical formulation of Vildagliptin or a pharmaceutically acceptable salt thereof, to be used for the treatment of Type2 diabetes.
  • the main objective of the present invention is to provide a formulation of Vildagliptin that is stable and robust and the manufacturing process is easy and cost effective.
  • Diabetes mellitus is a common disorder more prevalent in developed countries. It is a metabolic disease wherein an individual has high blood sugar level over a prolonged period of time. There are three types of the disease. In Type 1 diabetes the pancreas fails to produce enough insulin, therefore it requires immediate and life-long treatment with insulin. Type 2 diabetes is a chronic and progressive disease arising from a complex pathophysiology involving the dual endocrine defects of insulin resistance and impaired insulin secretion. The treatment typically begins with diet and exercise; however, it will be followed by oral antidiabetic monotherapy, before moving into a combination regime, because most patients find it hard to sufficiently control glycaemia during long-term treatment with diet and exercise alone.
  • DPP-rV Dipepidyl peptidase-IV
  • GLP-1 glucagon-like peptide- 1
  • incretin mimetic meglitinide and insulin.
  • DPP-IV inhibitors represent a class of agents that are being developed for the treatment or improvement in glycemic control in patients with type 2 diabetes.
  • Vildagliptin also known as LAF-237 is the generic name for (S)-l-[(3-hydroxy-l-adamantyl)amino]acetyl-2-cyano-pyrrolidine has been disclosed specifically in US patent no 6,166,063; it was introduced in 2006, it is easy to use and do not require regular glucose monitoring or dose adjustments.
  • Vildagliptin has been found to reduce fasting glucose and postprandial glucose excursion in association with significantly reduced HbAi c levels. It is well known in the art that DPP-IV inhibitors with primary or secondary amino group show incompatibilities, degradation problems or extraction problems with some excipients especially excipients that have acidic properties.
  • Vildagliptin has also a secondary amino group on its chemical structure. In solid dosage forms, it may react with many excipients or impurities of excipients. Although vildagliptin itself is very stable it has high susceptibility to air and humidity. This fact causes impurities to occur in the composition and leads to incorporation of undesired components into the composition.
  • EP 2468361 discloses a pharmaceutical composition, comprising vildagliptin granules which are coated with at least one coating layer and one or more than one excipients.
  • direct compression is used to develop tablet formulation of DPP-IV inhibitor compounds, especially vildagliptin or an acid addition salt thereof.
  • Vdagliptin is marketed under the trademark Galvus ® in 50 mg dosage forms by Novartis. It is indicated for the treatment of diabetes mellitus, but particularly in treating type 2 diabetes.
  • Galvus ® includes lactose anhydrose, microcrystalline cellulose, sodium starch glycolate and magnesium stearate.
  • the present invention relates to tablets, especially tablets formed by direct compression of a DPP-4 inhibitor compound, and a process for preparation thereof.
  • an object of the present invention to provide a pharmaceutical formulation comprising Vildagliptin or a pharmaceutically acceptable salt thereof formed by direct compression.
  • a further object of the present invention is to provide a manufacturing process that is easy and cost effective and overcomes the problems of impurities due to reaction of Vildagliptin to excipients present in the formulation.
  • Another aspect of the present invention is to provide a pharmaceutical formulation comprising Vildagliptin or pharmaceutically acceptable salt thereof, wherein the selection of excipients has been optimized and the production of impurities in the formulation has been minimized.
  • the main objective of the present invention is to provide a proper qualitative and quantitative composition of Vildagliptin or pharmaceutical acceptable salt thereof, prepared by a suitable manufacturing process in order to obtain a stable and efficacious dosage form with good physicochemical characteristics.
  • Another object of the present invention is to provide a pharmaceutical formulation comprising Vildagliptin or a pharmaceutically acceptable salt thereof and further comprising an appropriate amount of a disintegrant, wherein the disintegrant doesn't react with the active agent, and wherein the disintegrant is croscarmellose sodium.
  • a process for the preparation of a stable dosage form of Vildagliptin comprising an effective amount of a disintegrant and a combination of diluents, and a lubricant, which process comprises the steps of: blending the active agent with the disintegrant and the diluents, adding the lubricant and compressing into tablets.
  • the properties of the drug, its dosage forms and the economics of the operation will determine selection of the best process for tableting.
  • both wet granulation and direct compression are used in developing a tablet.
  • the dry granulation method may be used where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tabletted.
  • the method consists of blending, slugging the ingredients, dry screening, lubrication and compression.
  • the wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tableting.
  • the procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation.
  • the damp mass is then screened through a suitable screen and dried by tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill.
  • the overall process includes weighing, dry powder blending, wet granulating, drying, milling, blending lubrication and compression.
  • powders do not have sufficient adhesive or cohesive properties to form hard, strong granules.
  • a binder is usually required to bond the powder particles together due to the poor cohesive properties of most powders.
  • Heat and moisture sensitive drugs cannot usually be manufactured using wet granulation.
  • the large number of processing steps and processing time are problems due to high level manufacturing costs.
  • Wet granulation has also been known to reduce the compressibility of some pharmaceutical excipients, such as microcrystalline cellulose.
  • Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug.
  • the active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets.
  • the advantages of direct compression include uniformity of blend, few manufacturing steps involved, i.e., the overall process involves weighing of powders, blending and compression, hence less cost; elimination of heat and moisture, prime particle dissociation and physical stability.
  • direct compression is usually limited to those situations where the drug or active ingredient has physical characteristics required to form pharmaceutically acceptable tablets.
  • one or more excipients must often be combined with the active ingredient before the direct-compression method can be used since many ingredients do not have the necessary properties. Since each excipient added to the formulation increases the tablet size of the final product, manufacturers are often limited to using the direct-compression method in formulations containing a low dose of the active ingredient per compressed tablet.
  • a solid dosage form containing a high-dose drug i.e., the drug itself comprises a substantial portion of the total compressed tablet weight, could only be directly compressed if the drug itself has sufficient physical characteristics, e.g., cohesiveness, for the ingredients to be directly compressed.
  • DPP-IV inhibitors are considered a high- dose drugs.
  • Most tablet formulations include a range of 70-85% by weight of DPP-IV inhibitor per tablet.
  • This high-dose drug combined with its rather poor physical characteristics for direct compression, has not permitted direct compression as a method to prepare the final tablet.
  • the active ingredients have poor stability in presence of water, another factor militating against the use of the wet granulation method.
  • Another limitation of direct compression as a method of tablet manufacturing is the potential size of the compressed tablets. If the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active ingredient with other excipients to attain an acceptable sized tablet with the desired amount of active ingredient. The amount of filler, binder or other excipients needed in wet granulation is less than that required for direct compression since the process of wet granulation contributes toward the desired physical properties of the tablet
  • the present invention provides a direct tableting, free-flowing particulate Vildagliptin formulation in the form of a tableting powder, capable of being directly compressed into a tablet having adequate hardness, rapid disintegration time and an acceptable dissolution pattern.
  • Hydroxypropyl methylcellulose has been utilized in the pharmaceutical industry as a direct compression excipient for solid dose forms. Hydroxypropyl methylcellulose is a processed cellulose and controls drug release from solid dosage forms.
  • the tableting powder contains a number of inert materials known as excipients. They may be classified according to the role they play in the final tablet.
  • the primary composition includes fillers, binders or diluents, lubricants, disintegrants and glidants.
  • Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors in the case of chewable tablets.
  • excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed.
  • the preferred formulation of this invention comprises the following: Vildagliptin as the active ingredient, the binders or diluents which are microcrystalline cellulose and lactose, the disintegrant which is croscarmellose sodium and the lubricant which is magnesium stearate.
  • the excipients have been carefully selected after many optimization steps.
  • One, two, three or more diluents can be selected.
  • pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • the filler and/or diluent may be present in an amount from about 15% to about 40% by weight of the composition.
  • the preferred diluents include microcrystalline cellulose which is manufactured by the controlled hydrolysis of alpha-cellulose, obtained as a pulp from fibrous plant materials, with dilute mineral acid solutions. Following hydrolysis, the hydrocellulose is purified by filtration and the aqueous slurry is spray dried to form dry, porous particles of a broad size distribution. Suitable microcrystalline cellulose will have an average particle size of from about 20 nm to about 200 nm. Microcrystalline cellulose is available from several suppliers.
  • Suitable microcrystalline cellulose includes Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200, manufactured by FMC Corporation. Particularly preferred in the practice of this invention is Avicel PH 102, which has the smallest surface area and pore structure.
  • the microcrystalline cellulose is present in a tablet formulation in an amount of from about 25% to about 70% by weight, more preferably from about 30% to about 60% by weight; and most preferably from about 40% to about 50% by weight.
  • lactose is ground to have an average particle size of between about 50 ⁇ and about 500 ⁇ prior to formulating.
  • the lactose is present in the tablet formulation in an amount preferably from about 5% to about 40% by weight, more preferably from about 18% to about 35% by weight, and most preferred from about 20% to about 25% by weight.
  • a disintegrant is also an optional but useful component of the tablet formulation. Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. One, two, three or more disintegrants can be selected.
  • disintegrants examples include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone, cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium); soy polysaccharides; and guar gum, sodium starch glycolate.
  • the disintegrant e.g., may be present preferably in an amount from about 2% to about 20%, more preferably from about 5% to about 10%, and most preferably from 7% to about 9% by weight of the composition.
  • Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight.
  • the lubricant component may be hydrophobic or hydrophilic.
  • One, two, three or more lubricants can be selected.
  • Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • the lubricant may be present in an amount preferably from about 0.1% to about 5% by weight of the composition and most preferably from about 0.1% to about 2% by weight of the composition.
  • Magnesium stearate was the choice for the present invention. It reduces the friction between the die wall and tablet mix during the compression and ejection of the tablets. It helps prevent adhesion of tablets to the punches and dies. Magnesium stearate also aids in the flow of the powder in the hopper and into the die. It has a particle size range of 450-550 microns and a density range of 1.00-1.80 g/mL. It is stable and does not polymerize within the tableting mix.
  • solid fillers or carriers such as, cornstarch, calcium phosphate, calcium sulfate, calcium stearate, magnesium stearate, stearic acid, glyceryl mono- and distearate, sorbitol, mannitol, gelatin, natural or synthetic gums, such as carboxymethyl cellulose, methyl cellulose, alginate, dextran, acacia gum, karaya gum, locust bean gum, tragacanth and the like, diluents, binders, lubricants, disintegrators, coloring and flavoring agents could optionally be employed.
  • binders examples include, but are not limited to, starches; celluloses and derivatives thereof, e.g., microcrystalline cellulose, hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose; sucrose; dextrose; corn syrup; polysaccharides; and gelatin.
  • the binder e.g., may be present in an amount from about 10% to about 40% by weight of the composition.
  • composition as described above, wherein at least one diluent is a microcrystalline cellulose and wherein in the unit dosage form, the weight of Vildagliptin on a dry weight basis to tablet weight of microcrystalline cellulose ratio is of 1 to 3, preferably 1 to 2, most preferably of 1 to 1.80.
  • compositions as described above, wherein the weight ratio between diluent or combination of diluents and disintegrant, when the diluent is selected from lactose and/or microcrystalline cellulose and the disintegrant is selected from croscarmellose sodium is from 5: 1, preferably from 7.5: 1, more preferably is 10: 1.
  • Composition as described above comprising between 20 and 70mg Vildagliptin or a pharmaceutically acceptable salt thereof, preferably 50mg Vildagliptin or a pharmaceutically acceptable salt thereof.
  • vildagliptin used throughout the specification refers to not only vildagliptin per se, but also various pharmaceutically acceptable salts and pharmaceutically acceptable hydrates thereof.
  • the following Examples illustrate aspects of the present invention but are not in any way limiting the scope of invention.
  • the main objective is to develop a robust and stable immediate release tablet comprising vildagliptin.
  • the inventors first wanted to decide on the most appropriate manufacturing process. Therefore two different manufacturing processes were tested, dry mixing and wet granulation. All the excipients were selected with the perspective to enhance dissolution, physicochemical characteristics and stability of the drug substance in the final dosage form.
  • Composition 1 was prepared by dry mixing the internal phase excipients for 20 minutes and adding the external phase excipient and mixing for 3 minutes and the resulting tablets showed good characteristics with disintegration time of 3'01" ⁇ 30" (target disintegration time 30"- 5;00") and hardness of 105+5 N (target hardness 80-150N).
  • Composition 2 was prepared with wet granulation the internal phase excipients with water and drying the resulting granules and mixing the external phase excipient for 3 minutes and the tablets showed poor characteristics with disintegration time of 1 34+50" (target disintegration time 30"- 5;00") and hardness of 203+10N (target hardness 80-150N).
  • composition 1 is rather stable during the 6 months period, while Composition 2 exhibited high impurity levels over the specified limits. Moreover, Composition 1 exhibits the best behavior compared to the originator and according to the target characteristics, hence the dry mixing process (direct compression) was selected for the next formulation trials.
  • X 4 type of Disintegrant Crospovidone Croscarmellose sodium Table 9. DoE parameter settings including ingredients, proportion and type of excipients

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP18788663.5A 2017-10-03 2018-10-01 Pharmazeutische zusammensetzung mit vildagliptin und verfahren zur herstellung davon Active EP3691614B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20170100466A GR1009406B (el) 2017-10-03 2017-10-03 Φαρμακευτικο σκευασμα που περιλαμβανει βιλνταγλιπτινη και μεθοδος για την παρασκευη αυτου
PCT/EP2018/025254 WO2019068367A1 (en) 2017-10-03 2018-10-01 PHARMACEUTICAL COMPOSITION COMPRISING VILDAGLIPTIN AND METHOD FOR PREPARING THE SAME

Publications (2)

Publication Number Publication Date
EP3691614A1 true EP3691614A1 (de) 2020-08-12
EP3691614B1 EP3691614B1 (de) 2023-11-01

Family

ID=63878622

Family Applications (1)

Application Number Title Priority Date Filing Date
EP18788663.5A Active EP3691614B1 (de) 2017-10-03 2018-10-01 Pharmazeutische zusammensetzung mit vildagliptin und verfahren zur herstellung davon

Country Status (3)

Country Link
EP (1) EP3691614B1 (de)
GR (1) GR1009406B (de)
WO (1) WO2019068367A1 (de)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CO5150173A1 (es) 1998-12-10 2002-04-29 Novartis Ag Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv
ES2940341T3 (es) 2004-01-20 2023-05-05 Novartis Ag Formulación y proceso de compresión directa
GT200600008A (es) * 2005-01-18 2006-08-09 Formulacion de compresion directa y proceso
EA034049B1 (ru) * 2009-07-31 2019-12-23 КРКА, д.д., НОВО МЕСТО Гранулят, включающий вилдаглиптин, способ его получения и фармацевтическая композиция
TR201010683A1 (tr) 2010-12-21 2012-07-23 Sanovel İlaç San. Ve Ti̇c. A.Ş. Vildagliptin formülasyonları.
PL3512505T3 (pl) * 2016-09-16 2023-08-07 Galenicum Health S.L.U. Farmaceutyczne kompozycje wildagliptyny

Also Published As

Publication number Publication date
GR1009406B (el) 2018-11-26
WO2019068367A1 (en) 2019-04-11
EP3691614B1 (de) 2023-11-01

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